Mutations in HNF1A cause Maturity Onset Diabetes of the Young type 3, the second most frequent form of diabetes caused by single gene mutation. We generated human pancreatic stem cell-derived endocrine cells with mutations in HNF1A and show that HNF1A deficiency impairs sc-cell fate, insulin granule maturation and the secretion of insulin in a glucose responsive manner. Single-cell RNA sequencing reveals that HNF1A orchestrates a network of genes involved in glucose metabolism, zinc transport, calcium ion binding and hormone exocytosis. Furthermore, in both patients and stem cell-derived -cells, HNF1A deficiency altered the stoichiometry of secreted c-peptide to insulin. Sulfonylurea, used in the treatment of these patients, restored both insulin secretion and stoichiometry. Significantly, uncoupling of c-peptide and insulin secretion as described here questions the common practice in using c-peptide as a proxy to evaluate -cell function. We also demonstrate that correction of the HNF1A locus restores function, providing a path to cell therapy. SOURCE: Dieter Egli (de2220@cumc.columbia.edu) -  Columbia University

Pluto Bioinformatics

GSE129653: HNF1A deficiency impairs -cell fate, granule maturation and function (scRNA-seq of 271 hESC-derived cells: Differentiation day 25)